Iodine Consumption and Hashimoto's Thyroiditis: a Systematic Literature

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CALIFORNIASTATE UNIVERSITY SAN MARCOS

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TITLE: Hashimoto's Thyroiditis and Iodine Consumption

AUTHOR(S): Sandra Cracchiolo

DATE OF SUCCESSFUL DEFENSE: 04/23/2020

THE THESIS HAS BEEN ACCEPTED BY THE THESIS COMMITTEE IN

PARTIAL FULFILLMENTOF THE REQUIREMENTS FOR THE DEGREE OF

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Asherlev Santos May 4, 2020 COMMITTEECHAIR SIGNATURE DATE

Kathryn Hollenbach May 4, 2020 COMMITTEE MEMBER SIGNATURE DATE

COMMITTEE MEMBER SIGNATURE DATE

COMMITTEE MEMBER SIGNATURE DATE Iodine Consumption and Hashimoto’s Thyroiditis: A Systematic Literature Review

Sandra Cracchiolo

California State University San Marcos

IODINE AND HASHIMOTO’S THYROIDITIS 2

Abstract

Iodine deficiency is a global health problem that is affecting over 2 billion people worldwide and

50 million people are dealing with the health issues directly related to being iodine deficient.

The Universal Salt Iodization policy was created as a global initiative to eliminate iodine deficiency disorders worldwide and was implemented on a mandatory or voluntary basis.

Hashimoto’s thyroiditis is an autoimmune disease that attacks healthy thyroid cells by an antibody-mediated immune response. This disease affects 1.5 per 1000 worldwide and that number is continuing to increase. This systematic literature review examined previous studies to determine if an association exists between the prevalence of Hashimoto’s thyroiditis in relation to the levels of iodine consumption after universal salt iodization.

Keywords: Iodine, autoimmune thyroiditis, autoimmune disease, antibodies, Hashimoto’s thyroiditis, Universal Salt Iodization policy

IODINE AND HASHIMOTO’S THYROIDITIS 3

Acknowledgements

I would like to thank my committee for their continuous support throughout the development of my thesis. Thank you to my chair, Dr. Santos for always pushing me to dive deeper into my research. Thank you to Dr. Hollenbach for being my mentor, throughout this process as well in the professional world. Being able to work with you has taught me a great deal about what I want to further my career in, and I am truly grateful.

To my sister; my best friend; thank you for being there always, keeping my sane throughout this

entire process, and being my proofreader.

La mia tesi è dedicata alla mia famiglia, che ha lasciato tutto per venire in questo paese, per poter

avere una vita migliore. Soprattutto a mia Nonna che mi ha insegnato a inseguire sempre i miei

sogni senza arrendermi mai.

IODINE AND HASHIMOTO’S THYROIDITIS 4

List of Tables

Table 1. Studies with various iodine levels and Hashimoto’s thyroiditis

Table 2. Studies with iodine fortification and rates of Hashimoto’s thyroiditis

Table 3. Universal Salt Iodization Policy and Iodine Deficiency

IODINE AND HASHIMOTO’S THYROIDITIS 5

List of Figures

Figure 1. Recommended Dietary Allowance (RDA) for Iodine

Figure 2. Global Scorecard for Iodine Nutrition 2019

Figure 3. Flowchart for the first initial search in Systematic Literature Review

Figure 4. Flowchart for the second initial search in Systematic Literature Review

IODINE AND HASHIMOTO’S THYROIDITIS 6

Table of Contents

Abstract ...... 2 Acknowledgements ...... 3 List of Tables ...... 4 List of Figures ...... 5 Introduction ...... 7 Background ...... 9 Food Security ...... 9 Undernourishment...... 10 Overweight ...... 10 Micronutrients ...... 10 Global Policy ...... 14 Thyroid Function ...... 14 Hashimoto’s Thyroiditis ...... 16 Risk Factors ...... 17 Global Prevalence ...... 19 Socioeconomic Status ...... 20 Conceptual Framework ...... 21 Methods...... 22 Research Strategy ...... 22 Inclusion Criteria...... 22 Exclusion Criteria...... 23 Results ...... 23 Data Analysis ...... 23 Limitations ...... 38 Conclusion ...... 38 References ...... 40

IODINE AND HASHIMOTO’S THYROIDITIS 7

Introduction

Food insecurity is a global health issue that affects more than 700 million people. Food

availability, access, and utilization are the three factors that determine the level of security for

everyone. Countries that face higher levels of food insecurity are those affected by drought,

population size, war, low productivity, socioeconomic status, and disease. Malnutrition is one of

the consequences of food insecurity. It occurs from a lack of specific nutrients in the diet. In

2018, there were 165 million children under the age of five that are malnourished and the health issues that come with it. Malnutrition comes in three forms: undernourishment, overweight, and

micronutrient deficiencies.

Micronutrients are a combination of vitamins and minerals that are necessary for the

proper function of our immune system as well as the maintenance of healthy tissues. Since our

bodies do not produce micronutrients, the only way to get adequate amounts is through diet as

well as some supplements. Iron, vitamin A, vitamin D, folate, zinc, and iodine are some of the

micronutrients that people are the most deficient in which can be due to a poor diet or limited

access to healthy foods.

Iodine is essential for overall health, specifically for the production of thyroid hormones:

thyroxine (T4) and triiodothyronine (T3). Since the body does not produce iodine, it needs to be

supplemented by food; such as dairy, fish, eggs, and seaweed. If you are iodine deficient or

iodine excessive, your body can produce not enough or too much thyroid hormones which have

adverse effects on the body. The thyroid, heart, liver, kidney, muscles, and the brain are all at

risk for damage (Kapil, 2007). Approximately 2 billion people are suffering from Iodine

Deficiency Disorders (IDD) and 50 million are dealing with the health issues related to being

iodine deficient (Biban & Lichiardopol, 2017). IODINE AND HASHIMOTO’S THYROIDITIS 8

Hashimoto’s thyroiditis was first discovered by Dr. Hakaru Hashimoto as an organ-

specific autoimmune disorder affecting the thyroid. This disease progresses slowly, causing

chronic thyroid damage, and leads to a drop in thyroid hormone levels. In 2018, the global

incidence of Hashimoto’s thyroiditis was 0.3-1.5 cases per 1000 (Lee, 2018).

The Universal Salt Iodization (USI) policy was created as part of a global health initiative in 1994 to decrease the number of people that are iodine deficient (Doggui, et al., 2016). There has been a substantial decline in the amount of iodine deficient countries, however, more work

should be done to have all countries covered.

The globalization and population health framework are made up of the contextual, distal,

and proximal levels. The levels explain the relationship between the need for globalization,

global governance structures, and global effects of globalization on all aspects of population

health, especially on health(-related) policies.

The purpose of this thesis is to conduct a systematic literature review of existing literature

to determine if an association exists between the prevalence of Hashimoto’s thyroiditis in

relation to the levels of iodine consumption after universal salt iodization. The specific aim of

this thesis is to conduct a systematic literature review regarding the role that levels of dietary

iodine have on the prevalence of Hashimoto’s thyroiditis.

IODINE AND HASHIMOTO’S THYROIDITIS 9

Background

Food Security

Food security simply means that you regularly have plenty of food to eat. This is not true for over 10 million people (Gibson, 2012). UNICEF reported that in 2019, over 820 million people suffer from hunger. Food insecurity is constantly increasing in countries such as Africa,

Latin America, the Caribbean, and Western Asia.

Food security depends on three important factors: availability, access, and utilization. Those countries that have road and rail-way infrastructures seem to have a higher availability of food due to imports and domestic production. Access to those healthy foods is not only determined by availability but also an economic factor. Growing your food, earning a sufficient income, using the community or national levels as resources to obtain healthy food is achievable for some but not all. Utilizing the knowledge of basic nutrition and how that, along with having access to water and sanitation ensures that we are eating a healthy, well-balanced diet. Those countries that

are experiencing food insecurity are consuming more starchy foods and not enough protein, oils,

dairy, fruits, and vegetables which can lead to malnutrition and the health issues that arise from it

(Gibson, 2012).

Malnutrition

Malnutrition is just one of the issues that arise due to food insecurity. It can exist in three forms; undernourishment (wasting, stunting, underweight), overweight, and micronutrient deficiencies. Worldwide, there are 165 million children under the age of five that are malnourished (Asim & Nawaz, 2018). Everyone is at risk of being affected by malnutrition, but those that are in developing or underdeveloped countries are at a higher risk. Low- and middle- income countries reported about 45% of deaths among children under the age of 5 was due to IODINE AND HASHIMOTO’S THYROIDITIS 10

undernutrition (Malnutrition, 2018). Some of the consequences that occur are decreased muscle

function, decreased cardio-respiratory function, decreased gastrointestinal function, delayed

wound healing, decreased immune response, and psychosocial effects (Saunders & Smith, 2010).

Undernourishment

The World Health Organization states that there are three forms of undernourishment:

wasting, stunting, and underweight. Wasting is known as low weight-for-height, which usually

indicated that a person has not had enough food to eat or that they have had an infectious disease

that caused the weight loss (Malnutrition, 2018). Stunting is low height-for-age and is due to chronic undernutrition. These rates are higher in areas with poor socioeconomic conditions, and frequent illnesses. An underweight child has low weight-for-age and is usually stunted and wasted (Malnutrition, 2018).

Overweight

Another part of malnutrition is obesity. This occurs when a person is too heavy for their

height. According to the WHO, 1.9 billion adults and 40 million children are overweight or

obese (Malnutrition, 2018). This is due to unhealthy diets, poor nutrition, and access to healthy

foods. Heart disease, stroke, diabetes, and certain cancers are all consequences of obesity.

Micronutrients

Micronutrients play an important role in our metabolism, maintaining healthy tissues as

well as your immune system. The main way to get micronutrients is by eating a well-rounded

diet because the body cannot produce these vitamins and minerals. However, some of these

micronutrients can be supplemented by vitamins. Micronutrients are divided into four

categories: water-soluble vitamins, fat-soluble vitamins, macrominerals, and trace minerals. IODINE AND HASHIMOTO’S THYROIDITIS 11

Iron, vitamin A, vitamin D, folate, zinc, and iodine tend to be the micronutrients that people are

most deficient in.

Iron

Iron is essential in hemoglobin which helps bring oxygen around your body. The recommended dosage is 7 – 18 mg per day and 27 grams for pregnant women. Iron is mostly found in animal products, beans, and supplements. According to the WHO, iron deficiency is

the most common nutritional disorder affecting developing and developed countries. This

disorder affects over 2 billion people, especially those countries that have a higher rate of

infectious diseases. The repercussions of this are poor pregnancy outcomes, impaired physical

and cognitive development, and increase risk in morbidity in children (Abu-Ouf & Jan, 2015).

Vitamin A

Vitamin A is important for a healthy immune system, vision, growth, and development.

Vegetables are extremely high in vitamin A and can also be supplemented with a daily vitamin.

Being deficient in vitamin A poses another global health issue. Low-income countries such as

Africa and South-East Asia are at a higher risk for developing blindness, disease, and death related to infections due to being vitamin A deficient. The WHO estimates the 250,000 to

500,000 vitamin A deficient children go blind each year and half of those children die within a year of losing their eyesight (Boyd, 2020).

Vitamin D

Vitamin D is necessary for the proper function of the parathyroid glands, which work to balance the calcium in the blood. It also aids in the regulation of over 200 genes and is essential

for growth and development (Naeem, 2010). This vitamin is absorbed by food, supplementation

as well as sun exposure. A weakened immune system, severe bone loss, hair loss, and muscle IODINE AND HASHIMOTO’S THYROIDITIS 12

pain are some of the symptoms that can occur due to being deficient in vitamin D (Naeem,

2010). Countries in the Middle East tend to be the most at risk; with 50% to 80% of the

population being deficient (Naeem, 2010).

Folate

Folate is a type of vitamin B that is necessary for the production of red blood cells as well as making and repairing DNA. A diet low in fresh fruits and vegetables can lead to the

development of folate deficiency. Complications that arise due to a folate deficiency are

megaloblastic anemia, low levels of white blood cells, and serious birth defects of a developing

fetus (Khan, 2019).

Zinc

Zinc is used for cellular production as well as supporting your immune system. It is also important in the creation of DNA. Multivitamins, along with diet are ways to ensure that you are getting the correct amount of Zinc (Wessells & Brown, 2012). The WHO reported that 16% of lower respiratory tract infections, 18% of malaria, 10% of diarrheal disease, and 0.8 million deaths are due to zinc deficiency (World Health Organization, 2010).

Iodine

Iodine is a micronutrient that is necessary for the overall health and wellbeing of a population, but it is especially important for fetal and early childhood development. Iodine is mostly found in food. Seafood and edible seaweed are rich in iodine because marine animals can concentrate the iodine from seawater (Iodine, 2019). Dairy, eggs, fruit, grains, and poultry are other good sources of dietary iodine (Iodine, 2019). Iodine is also found in soil, but the amount of iodine depends on the type of soil and location of that soil (Iodine, 2019). In iodine-rich soil, the iodine concentrations of plants can be as high as 1000 ug/kg, but in iodine-deficient soil, it IODINE AND HASHIMOTO’S THYROIDITIS 13

can be as low as 10 ug/kg (Leung, et al., 2012). For example, in the United States, dairy

products contribute up to 90% of the total estimated iodine intake in infants (Iodine, 2019). In the UK and northern Europe, iodine levels in diary are lower in the summer because cattle are grazing in pastures with low soil iodine content (Iodine, 2019).

Iodine fortification programs have been implemented to help lower iodine deficiency in areas around the world (Leung, et al., 2012). This fortification program has created mandatory iodization of all food-grade salt with iodine in 120 countries (Leung, et al., 2012). In the United

States, this is voluntary, and the FDA does not require the iodine content to be placed on food packaging (Leung, et al., 2012).

The World Health Organization has criteria on the Recommended Dietary Allowance

(RDA) for iodine for different life stages, ages, and gender (Figure 1). For example, adults require 150 ug/day and children require about 120 ug/day for proper iodine nutrition.

Iodine Deficiency

Iodine deficiency can occur in three forms: mild, moderate, or severe. The health consequences of iodine deficiency depend on the level of iodine deficiency and can be extremely dangerous. Pregnant women must have an adequate level of iodine intake, especially within the first sixteen weeks. The health consequences to a developing fetus include an increased risk of miscarriage, stillbirths, cretinism, and an increase in infant mortality. When the body is mildly iodine deficient some effects are tiredness, weight gain, achy muscles, dry skin, and brittle nails.

Severe iodine deficiency results in brain damage, goiter, difficulty breathing, irreversible thyroid damage, coma, impaired mental and physical development.

IODINE AND HASHIMOTO’S THYROIDITIS 14

Global Policy

The Universal Salt Iodization (USI) policy was implemented as a global health initiative

in 1994 with the hope of increasing iodine intake (Doggui, et al., 2016). This policy has been

implemented in many countries; however, one-third of the global population is still suffering

from ID (Andersson, et al., 2012). In some countries, such as the United States, this policy is

voluntary (Maalouf, et al., 2015). When this policy was implemented, there have been

improving rates of iodine deficiency. In 1993, 110 countries were iodine deficient. In 2012, due

to the implementation of the policy, 32 countries were iodine deficient (Andersson, et al., 2012).

It may seem that this policy is making an impact in improving the global issue of iodine

deficiency; 241 million SAC (school-aged children) are still iodine deficient (Andersson, et al.,

2012). Southeast Asia continues to have the largest number of SAC with iodine deficiency (76

million) and Africa has 58 million SAC that is iodine deficient (Andersson, et al., 2012).

Thyroid Function

For a thyroid to function correctly about 70-80% of the iodine, which amounts to 120

micrograms (mcg), is used by the thyroid for the production of thyroid hormones (Ahad &

Ganie, 2010). The thyroid is an important factor in the metabolism of iodine. The thyroid gland

consists of two lobes that are located on either side of the trachea (Zbigniew, 2017). It is a

relatively small organ, measuring about 4 cm long and 2 cm thick but is the largest endocrine

gland in the body (Zbigniew, 2017). The thyroid takes more blood per unit than the kidneys

through the superior and inferior thyroid arteries (Zbigniew, 2017). The part of the thyroid that is responsible for the metabolism of iodine is the follicle. The follicle is made up of a protein-

rich material that contains a glycoprotein called thyroglobulin (Zbigniew, 2017). IODINE AND HASHIMOTO’S THYROIDITIS 15

The first step in the metabolism of iodine is iodine trapping, which starts from the

capillary thyroid cells and transports it to the follicular cells by active transport and the Na+;-K

pump (Ahad & Ganie, 2010). Within the follicular cells, thyroglobulin, which is used as the

substrate to synthesize thyroid hormones, is synthesized and secreted into the follicular lumen.3

Then the oxidation of iodide begins. The iodide enters the follicular lumen by a sodium

independent iodide/chloride transporter called pendrin (Ahad & Ganie, 2010). When the iodide

enters the follicular lumen, it is immediately oxidized from iodide to iodine (Ahad & Ganie,

2010). Once that process is complete, the hypothalamus sends thyroid-stimulating hormone

(TSH) to the pituitary gland which stimulates the thyroid to produce thyroid hormones

(Zbigniew, 2017). TSH then reacts with the thyroglobulin to produce the thyroid hormones;

tetra-iodothyronine (T4) and tri-iodothyronine (T3) (Zbigniew, 2017).

If too much iodine is consumed; iodine poisoning; the synthesis of thyroid hormones

becomes inhibited, which causes a decrease in TSH, an increase in T3 and T4, and leads to

iodine-induced hyperthyroidism (Zbigniew, 2017). If too little iodine is consumed, an excess of

TSH is released into the bloodstream which causes a decrease in T3 and T4 (Zbigniew, 2017).

The excess of TSH causes hypothyroidism (Zbigniew, 2017). According to the Mayo Clinic, normal TSH levels range from 0.4 to 4.0 mU/L and anything above or below those values can signify an issue. Anything below 0.4 mU/L is a sign of hyperthyroidism and anything higher than 4.0 mU/L can alert physicians to hypothyroidism (Hashimoto’s Disease, 2018). One of the signs of goiter is visible swelling in the front of your neck which if left untreated can affect breathing and swallowing. The main symptoms of hypothyroidism are fatigue, increased sensitivity to cold, unexplained weight gain, and depression (Noureldine & Tufano, 2015).

IODINE AND HASHIMOTO’S THYROIDITIS 16

Hashimoto’s Thyroiditis

Hashimoto’s Thyroiditis is an autoimmune disease that destroys thyroid cells by an

antibody-mediated immune process (Mincer & Jialal, 2018). This disease has many names such

as; chronic autoimmune thyroiditis and chronic lymphocytic thyroiditis. Hashimoto’s

Thyroiditis involves the formation of antithyroid antibodies that attack the thyroid tissue (Mincer

& Jialal, 2018). A simple blood test is done to determine thyroid-stimulating hormone levels.

The biggest issue with this disease is the late prognosis. With this disease it is important

to start treatment as soon as possible, but that it is difficult because diagnosis is challenging and

does not occur until it has progressed (Mincer & Jialal, 2018). To detect Hashimoto’s

Thyroiditis, bloodwork and ultrasounds are important. Doctors check for an elevated thyroid-

stimulating hormone (TSH), and low thyroxine (T4) levels with anti-thyroid peroxidase (TPO)

antibodies (Mincer & Jialal, 2018).

Hashimoto’s thyroiditis affects women more than men by 10:1 and is usually diagnosed

between 30 to 50 years old (Mincer & Jialal, 2018). Currently, Hashimoto’s Thyroiditis affects

1.5 people per 1000 people and that number is continuing to rise. Even though there are no

symptoms of Hashimoto’s, there are symptoms for goiter and hypothyroidism; which are

complications of this disease. There can be a delay in diagnosis since a blood test measuring

TSH is not routinely done.

According to the Mayo Clinic, there is no cure for Hashimoto’s Thyroiditis, but it is

manageable. Once a patient is diagnosed with Hashimoto’s Thyroiditis, a synthetic thyroid

hormone, levothyroxine is then prescribed. Synthetic levothyroxine is a replacement for

thyroxine, a hormone that is naturally produced by the thyroid. This medication is given orally,

used to restore adequate hormone levels, and is a life-long treatment. It is best to take first thing IODINE AND HASHIMOTO’S THYROIDITIS 17

in the morning on an empty stomach and you should wait six hours before taking another

supplement to improve absorption. Since Hashimoto’s Thyroiditis is more common in women,

the dosage needs to be increased by 30% if pregnant. As with all medications, there are side

effects. Excessive amounts of levothyroxine can accelerate bone loss and arrhythmias, which is

why constant blood work is necessary to monitor your TSH levels.

The main reason to investigate iodine in relation to Hashimoto’s thyroiditis is that if gone

untreated, this disease can cause detrimental health effects; such as cancer. Studies have shown

an association with Hashimoto’s thyroiditis and an increased prevalence of papillary thyroid

cancer and malignant thyroid lymphoma (Noureldine & Tufano 2015).

Risk Factors

Factors that may contribute to the rates of Hashimoto’s thyroiditis are sex, pre-existing

conditions, genetics, and environmental triggers. Developing this disease is seven times more

likely to develop in women than men. This can be due to the number of immune-related genes

that are associated with the X chromosome (Zaletel & Gaberscek, 2011). Having other

autoimmune diseases such as, rheumatoid arthritis, type 1 diabetes, or lupus increases the risk of

developing Hashimoto’s thyroiditis due to a shared gene that predisposes people for these

diseases (Godman, 2018).

Genetic factors account for 80% of the likelihood of developing Hashimoto’s thyroiditis

and environmental triggers account for 20%. These genes assist the immune system in

distinguishing the body’s proteins from viruses and bacteria (Zaletel & Gaberscek, 2011). Six

autoimmune thyroid disease (AITD) susceptible genes are HLA-DR, CD40, cytotoxic T lymphocyte-associated factor (CTLA-4), protein tyrosine phosphatase 22 (PTPN22), thyroglobulin (Tg) and thyroid-stimulating hormone receptor (TSHR) (Tomer & Huber, 2009). IODINE AND HASHIMOTO’S THYROIDITIS 18

Environmental factors such as iodine intake, drugs, infections, and chemicals can contribute to

the development of Hashimoto’s thyroiditis (Zaletel & Gaberscek, 2011). Levels of iodine deficiency and excessive levels of iodine have been shown to affect thyroid autoimmunity.

According to Zaletel, a slight change in the daily recommended dose of iodine consumed can induce an autoimmune response. This occurs when the transcriptional signature on immune cells is altered which can induce a cytokine and chemokine response (Bilal, et al., 2017). Iodine can affect thyroid autoimmunity by creating iodine-containing epitopes that enhance the binding of the T-cell receptors which can lead to specific T-cell activation on certain genes (Zaletel &

Gaberscek, 2011). Low levels of iodine consumption can increase the risk of Hashimoto’s thyroiditis in those that are predisposed. Iodine deficiency can cause a dysfunction in the production of hormones which can trigger an autoimmune response. High levels of iodine consumption can also increase the risk of Hashimoto’s thyroiditis in predisposed individuals.

When too much iodine is consumed, the healthy thyroid cells undergo oxidative damage which

causes inflammation. This inflammation causes the expression of the intracellular adhesion

molecule-1 (ICAM-1) on the thyroid cells occurs which can attract immune cells to the thyroid

(Zaletel & Gaberscek, 2011). An immune shift occurs which causes autoimmunity against the thyroid cells.

Drugs that are used to treat chronic hepatitis, melanoma, and renal carcinoma have been

shown to trigger Hashimoto’s thyroiditis in susceptible individuals (Zaletel & Gaberscek, 2011).

Infections such as parvovirus, rubella, herpes simplex virus, Epstein Barr virus, and human T-

lymphotropic virus have been shown to release pro-inflammatory mediators that may lead to the

activation of T-cells (Desailloud & Hober, 2009). Certain chemicals such as polyaromatic

hydrocarbons or polyhalogenated biphenyls that are used for industrial applications have been IODINE AND HASHIMOTO’S THYROIDITIS 19 shown to trigger thyroid autoimmunity. A study in Brazil showed a significantly high prevalence of Hashimoto’s thyroiditis in those that live close by a petrochemical complex of Sao

Paolo compared to the control group (Zaletel & Gaberscek, 2011).

Genetics and environmental triggers can increase antigen presentation in those that are susceptible by reducing an immune tolerance, cytokines are produced that trigger apoptosis and activation of immune cells which leads to the destruction of healthy thyroid cells.

Global Health Implications

Many global health implications are a consequence of iodine deficiency. The population that is most at risk are pregnant mothers, fetuses, newborns, and young infants. Mild iodine deficiency can cause thyroid failure, intellectual, motor, and hearing deficits. In more severe levels of deficiency; cretinism, stillbirth, miscarriage, and increase in infant mortality can occur.

Hashimoto’s thyroiditis has its own set of implications. If not treated, it can increase the risk of developing heart conditions, congenital defects, depression, and cancer which can place a finical burden on a family.

Global Prevalence

The International Council for Control of Iodine Deficiency Disorders (ICCIDD) stated that there is a high global prevalence of iodine deficiency and Hashimoto’s Thyroiditis. These disorders create mental and physical consequences which in turn place an economic and human burden that can be prevented (Eastman, 2012). In 2017, it was reported that approximately 2 billion people are suffering from iodine deficiency and 50 million people have illnesses directly related to being iodine deficient (Biban & Lichiardopol, 2017). South Asian and sub-Saharan

African countries have higher rates of iodine deficiency than other parts of the world

(Zimmerman, 2008). The Iodine Global Network created a global scorecard of iodine levels in IODINE AND HASHIMOTO’S THYROIDITIS 20

school-aged children. Figure 2 shows that 25 countries are still iodine deficient and 14 countries are reporting excessive levels of iodine (Global Scorecard, 2019). Currently, only 71% of the world’s population is covered under a program to combat the worldwide deficiency concern, however, the rates of Hashimoto’s Thyroiditis are increasing as well. With the worldwide population being 7.7 billion people and the annual incidence of Hashimoto’s Thyroiditis is 1.5 cases per 1000 people more research is needed to determine if an association exists (Hashimotos,

2018).

Socioeconomic Status

To determine if socioeconomic status plays a role in iodine nutritional status, a study was

completed in Kolkata, India to compare iodine nutrition among school-age children (SAC) in

high-socioeconomic groups (HSGs) and low-socioeconomic groups (LSGs). The study

compared the median urinary iodine (MUI) from 2875 SAC from an HSG and 2440 SAC from

an LSG (Bhattacharya & Chandra, 2019). It was found that those in the LSGs were mildly iodine

deficient and the HSGs were at risk of developing iodine induced thyroid diseases. This study

found that socioeconomic status plays an essential role in iodine nutrition even after salt

iodization has been implemented.

Another study in Germany was done to determine if the German iodine fortification

program reached all socioeconomic groups. This was a population-based study that included

4056 adults for cross-sectional and 2860 adults from longitudinal analysis (Völzke, et al., 2013).

They found that those in the higher socioeconomic status had larger thyroid volumes, but these

associations did not have a statistical significance. Overall, between the socioeconomic statuses,

there was no impact on iodine supply and the prevalence and incidence of thyroid disorders. IODINE AND HASHIMOTO’S THYROIDITIS 21

In Brazil, a cross-sectional study was conducted to determine if socioeconomic status played a role in iodine nutritional status among school-aged children in Bahia. They discovered that the risk of iodine deficiency was increased by 70% in schoolchildren who had moderate or severe food insecurity (Campos, et al., 2016).

Globalization

Iodide fortified goods are traded due to the movement of food across borders. The countries that have a higher socioeconomic status tend to have a more dynamic marketplace and those that have a lower socioeconomic status continue to receive poor quality food which results in poor diets (Hawkes, 2007). Aside from the difference in diets, there is no way to regulate the number of iodized goods that are being consumed (Andersson, 2007, p.35). This can cause an increase in the rates of iodine deficiency or excessive iodine intake, which in turn can damage the thyroid.

Conceptual Framework

Huynen’s globalization and health conceptual framework are made up of three levels; contextual, distal, and proximal. These levels show the intralevel relationships between them and their role on population health. Health policy, trade, and lifestyle are all factors that contribute to population health with iodine fortification. The contextual (e.g. institutional and economic), distal (e.g. health-related policy), and proximal (e.g. food and water) determinants of globalization have a direct and indirect impact on iodine nutrition. The World Health

Organization along with UNICEF were responsible for creating the Universal Salt Iodization policy to decrease the amount of iodine deficiency disorders worldwide. Since economic development has increased, about 20% of the world’s output is being traded (Huynen, et al.,

2005). Food trade is an important factor in improving food security. The proximal level of this IODINE AND HASHIMOTO’S THYROIDITIS 22 framework is food and water which focuses on the individuals’ diet. However, since the

Universal Salt Iodization policy is not mandatory worldwide, there is no regulation on the amount of iodine being consumed which can lead to an increase in iodine related disorders.

Methods

A systematic literature review was conducted to identify if an association exists between the prevalence of Hashimoto’s Thyroiditis in relation to the level’s iodine consumption

(excessive, adequate, or deficient). The primary investigator reviewed each title and abstract to determine if each article contained the necessary information. A meta-analysis was attempted, but due to the high heterogeneity and diversity in the studies, it could not be completed.

Research Strategy

The databases used to search peer-reviewed articles included PubMed, PubMed Central,

Science Direct, and PLOS. Specific terms that were used for this search included; iodine levels, universal salt iodization policy, humans, autoimmune thyroiditis, Hashimoto’s thyroiditis, and antibodies.

Inclusion Criteria.

Inclusion was limited to systematic reviews and studies that examined iodine levels and

Hashimoto’s thyroiditis. The articles that were included in this search were published between

1998 and 2020. The literature search was completed between May 2019 and February 2020, by the use of the selection criteria. Studies that were performed outside the United States were also considered. Studies in populations with deficient, adequate, and excessive iodine consumption were included. This review included studies that compared the rates of Hashimoto’s thyroiditis before the implementation of the Universal Salt Iodization policy as well as after the implementation of the policy. Articles were used for this literature review if they mentioned IODINE AND HASHIMOTO’S THYROIDITIS 23 iodine deficiency, adequate iodine levels, excessive iodine levels, Hashimoto’s thyroiditis, urinary iodine concentration, universal salt iodization, and antibodies.

Exclusion Criteria.

Any articles that were published before 1998, studies and literature reviews with misleading titles and abstracts were excluded. While reviewing the literature, articles were removed if the studies were completed on animals instead of humans. Articles were also removed if they did not mention iodine levels and rates of Hashimoto’s thyroiditis or the antibodies associated with the disease. Upon further investigation, articles were removed if they mentioned other thyroid diseases such as goiter and not Hashimoto’s thyroiditis.

Results

Data Analysis

This systematic literature review analyzed literature that discussed the prevalence between iodine levels and Hashimoto’s thyroiditis.

Two separate searches were used for this literature review. The first initial search strategy used PubMed, PubMed Central, Science Direct, and PLOS began by using “iodine levels” which yielded 453,285 articles. Duplicates were excluded which brought the number of articles to 453,256. The time frame of 1998 – 2020 was then inputted to the search which reduced the number of articles to 371,557. Next, articles were eliminated if they did not mention that humans were involved in the research which brought the number of articles used to 72,467.

Search terms “autoimmune thyroiditis AND Hashimoto’s thyroiditis AND antibodies” were also added to the search which lowered the number of articles to 877. Finally, articles were eliminated based on misleading titles and abstracts which lead to the final number of articles used to 7. Articles were then organized into two tables; the first table included articles that IODINE AND HASHIMOTO’S THYROIDITIS 24 showed how regions of iodine deficiency, adequate iodine, and excessive iodine consumption play a part in the rates of Hashimoto’s thyroiditis. The second table includes studies that researched how the implementation of the Universal Salt Iodization policy has affected the rates of Hashimoto’s thyroiditis.

Figure 3. Flowchart for the first initial search in Systematic Literature Review

Steps on the flow chart 1. Identification a. Articles identified through the database (n=453,285) b. Duplicates removed (n=1,029) 2. Screening a. Articles screened (n=452,256) b. Records excluded (n=452,249); based on date (n=80,699), based on research strategy (n=370,680), based on abstract/title (n=870) IODINE AND HASHIMOTO’S THYROIDITIS 25

3. Included a. Articles used in the systematic review (n=7) Table 1. Studies with various iodine levels and Hashimoto’s Thyroiditis

Study Country Objective Methods Results Conclusion (Laurberg, 1998) Iceland & To study the Comparative Study. TSH: Iceland: 150 Both low and Denmark importance of ug/L high iodine population iodine Age: 66-70 year- Denmark: 38 ug/L intake levels intake level and old TgAB/TPOAB: correlate to a the prevalence of Iceland: n: 100 Twice as high in high prevalence various thyroid High iodine levels Denmark than rate of thyroid abnormalities in Denmark: n: 423 Iceland abnormalities. elderly subjects. Low iodine levels P < 0.01 Twice as high in women in both countries P < 0.05 (Teng, 2006) China To examine the Five year follow up Prevalence of More than effect of regional study. (1999 – autoimmune adequate or differences in 2004) thyroiditis differed excessive iodine intake on significantly among iodine intake the incidence of Three regions with the three countries may lead to thyroid disease. different iodine x2 = 18.4, P <0.001 hypothyroidism levels: Panshan, and mildly deficient; between Panshan and autoimmune Zhangwu, more Zhangwu thyroiditis. than adequate; and x2 = 8.7, P = 0.003 Huanghua, excessive. between Panshan and Huanghua x2 = 18.8, P < 0.001

no significance between Zhangwu and Huanghua x2 = 3.6, P = 0.06 (Premawardhana, Sri Lanka To determine if 367 schoolgirls. Median urine Iodine et al., 2000) iodine deficiency 11-16 years old. concentrations concentrations was the likely ranged from 105 – and thyroid cause of a high Thyroid 152 ug/l. function show prevalence in Sri ultrasounds, TgAb, that iodine Lankan TPOAb and Urine TgAb was raised deficiency is schoolchildren. iodine P < 0.03 not a problem, concentrations. but excessive TPOAb was 10% or iodine is. less.

Iceland and Denmark

This comparative study was completed in 1998 and included two different countries;

Iceland and Denmark. Iceland was reported to have high levels of iodine intake and Denmark had low levels of iodine. Random elderly subjects were selected from each country; Iceland (n =

100) and Denmark (n = 423). This study showed that TPO-Ab and Tg-Ab were twice as IODINE AND HASHIMOTO’S THYROIDITIS 26

common in females than in males (P < 0.05) in both Iceland and Denmark (Laurberg, et al.,

1998). It was also noted that both antibodies were twice as common in Denmark than in Iceland

(P < 0.01) (Laurberg, et al., 1998). Laurberg states that this study has shown that both low and high iodine intake levels correlate to a high prevalence of thyroid abnormalities.

China

A cross-sectional study in China looked at 3,018 participants in three different regions;

Panshan, Zhangwu, and Huanghua (Teng, et al., 2009). Each region was chosen because of the different levels of iodine intake. The Panshan region is in the northeastern part of China and is usually mildly iodine deficient. Another northeastern country, Zhangwu was mildly iodine deficient before this study, then in 1996 reached an adequate level of iodine. Huanghua, a country that is close to the Bo Hai Sea is iodine excessive (Teng, et al., 2009). There were two parts to this study; the baseline that was completed in 1999 and the follow-up was completed in

2004. Oral questionnaires were given to all the residents of each country that were older than 13 years of age and those that have been living there for more than 10 years (Teng, et al., 2009).

The only exclusion criteria were pregnant women and those receiving oral contraceptives. In

1999 there were 3,761 participants and 3,018 in 2004. Median urinary iodine, levels of thyroid hormones, and thyroid antibodies from each individual were tested. In this study, Teng, Shan, &

Teng reported that the prevalence of autoimmune thyroiditis differed significantly among the three countries (x2 = 18.4, P <0.001), between Panshan and Zhangwu (x2 = 8.7, P = 0.003) and

between Panshan and Huanghua (x2 = 18.8, P < 0.001). However, there was no significance

between Zhangwu and Huanghua (x2 = 3.6, P = 0.06). It was shown that those with antithyroid

antibodies at baseline showed an increase in the antibodies in the Zhangwu and Huanghua

regions of China (Teng, et al., 2009). IODINE AND HASHIMOTO’S THYROIDITIS 27

Sri Lanka

After mandatory salt iodization, a study with 367 schoolgirls aged 11 – 16, was done in

Sri Lanka to monitor the effects. Thyroid ultrasounds, thyroid levels, TgAb, TPOAb, and urine iodine concentrations were measured. They found an increase in the prevalence of TgAb in all age groups, but they noted a statistically significant difference in the girls between the ages of 13 and 12 (P < 0.05) (Premawardhana et al., 2000).

Three years later a follow-up study was conducted to re-evaluate thyroid autoimmunity.

This study had a total of 282 schoolgirls that were evaluated in the same way as the previous study. The results showed a significantly lower prevalence of TgAb in 2001 than in 1998 (P <

0.001).

Table 2. Studies with iodine fortification and rates of Hashimoto’s Thyroiditis

Study Country Objective Methods Results Conclusion (Rink, et al., 1999) Germany To determine the Two groups. One Group that Higher doses of effect of iodine treated with iodine, received 1.53 mg iodine cause and fortification on one with of iodine/week increase in Hashimoto’s Hashimoto’s saw 4x higher Hashimoto’s, Thyroiditis Thyroiditis incidence of however a low- Hashimoto’s daily dose is more Thyroiditis sustainable (Zimmermann, et Morocco To determine is Rif Mountains in Significant No patients al., 2003) introduction of northern Morocco. increase in thyroid developed clinical iodized salt antibodies at the evidence of thyroid induces thyroid Severely iodine 20- and 40-week autoimmune autoimmunity. deficient. check P < 0.0001 disease.

and after after (C2) (2004- Tg-Ab: introduced in mandatory 2005) C1: 13.7% Denmark. iodization of salt. C2: 19.9% P < 0.001 (Lombardi, 2013) Italy To verify the 1995: n: 1,411 1995: Iodine: 55 Iodine intake effects of voluntary 2010: n: 1,148 ug/L TgAb: 12.6% strongly affected iodine prophylaxis Excluded: HT: 3.5% the pattern of in a small rural Subjects with thyroid diseases. community positive 2010: Iodine: 98 (Pescopagano, TgAB/TPOAB. ug/L The benefits of Italy) Pregnant/lactating TgAb: 19.5% correcting iodine women. HT: 14.5% deficiency far . outweigh the risk P < 0.0001 of developing thyroid autoimmunity.

Germany

In 1999, a study measuring the effect of iodine on Hashimoto’s thyroiditis was completed in Germany. There were two groups to this study; group one had 375 euthyroid patients and group two had 377 patients that were diagnosed with Hashimoto’s thyroiditis. Group one was split into three separate groups; the first received daily doses of 200 mcg of iodide, the second received weekly doses of 1.53 mg of iodide, and the last group was not treated (Rink, et al.,

1999). No significant increase was found in the group that took the 200 mcg/day but there was a significant increase in the group that took the 1.53 mg of iodine weekly. It was found that the incidence of Hashimoto’s thyroiditis was 4-fold higher than in the other two groups (Rink, et al.,

1999).

Morocco

In 2003, a prospective trial was done involving school-age children in a region of

Morocco that is known to be severely iodine deficient. A total of 323 children, ages ranging from

6 to 15 years old were included. This study took place over a one-year time period and blood and urine samples were collected to create a baseline. According to Zimmermann, each participant was given 2 kg of iodized salt each month for a year. Blood work, urine samples, height, and weight were taken at the 10, 20, 40- and 52-week marks (Zimmermann et al., 2003). IODINE AND HASHIMOTO’S THYROIDITIS 29

At the beginning of this study, all subjects had median urinary iodine of 17 ug/l which increased

to 150 – 200 ug/l at the end (Zimmermann et al., 2003). It was noted that there was a significant increase in thyroid antibodies at the 20- and 40-week check (P < 0.0001). In result, only 1% of the children had elevated levels of TPO-Ab but did not develop Hashimoto’s thyroiditis while

the other children’s TPO-Ab returned to baseline (Zimmermann et al., 2003).

Denmark

Two identical cross-sectional studies were conducted in Denmark comparing the concentrations of thyroid antibodies before and after the mandatory iodization of salt (Pedersen, et al., 2011). This study focused on two cities; Aalborg and Copenhagen. In 1997, Cohort 1(C1) was made up of 4,649 participants. After 5 years, 3,570 participants made up Cohort 2 (C2).

Both cohorts included men and women from all age groups, the only exclusion criteria were those that take iodine supplements. Blood and urine samples were collected both times and were analyzed blind. Before iodine fortification, the median urinary iodine was 45 ug/l in Aalborg and 61 ug/l in Copenhagen (Pedersen, et al., 2011). After 5 years, the median urinary iodine increased to 86 ug/l in Aalborg and 99 ug/l in Copenhagen (Pedersen, et al., 2011). The results showed that the overall prevalence of thyroid antibodies (TPO-Ab and/or Tg-Ab) was significantly higher after iodine fortification. The levels of TPO-Ab in C1 were 14.3% and in C2 was 23.8%; the levels of Tg-Ab in C1 were 13.7% and C2 was 19.9% (Pedersen, et al., 2011).

Italy

In 2013, a study to evaluate the effects of voluntary iodine prophylaxis occurred in

Pescopagano, Italy. This community survey had a total of 1,411 participants in 1995 and 1,148 participants in 2010. The only exclusions to this study were those that had a medical history of

TgAB/TPOAB in their blood. Questionnaires, thyroid ultrasounds, thyroid function tests, and IODINE AND HASHIMOTO’S THYROIDITIS 30 urinary iodine concentrations were done to set a baseline. In 1995, the questionnaire revealed that none of the subjects reported using iodized salt (Lombardi, et al., 2013). However, in 2010,

65.9% of those participants reported using iodized salt on a daily basis (Lombardi, et al., 2013).

The results showed that the UIE was significantly higher in 2010 than in 1995 (P < .0001)

(Lombardi, et al., 2013). When thyroid antibodies were tested, they noted a significant increase in the levels of TgAB from 1995 (12.6%) to 2010 (19.5%, P < .0001). Another significant increase was in the prevalence of Hashimoto’s thyroiditis. In 1995, the percentage of those that had Hashimoto’s thyroiditis was 3.5% and in 2010, 14.5% (P < .0001) of the participants were diagnosed.

The second search strategy also used PubMed, PubMed Central, Science Direct, and

PLOS. Using “Universal Salt Iodization policy” yielded 6,100 articles. Once duplicates were removed that number dropped to 6,098. A date range of articles published between 1998-2020 was added to the search which yielded 6,073. The search terms “thyroid” was added along with

“Universal Salt Iodization policy” which generated 242 articles. “Antibodies” was also added to the search with yielded 66 results. Articles were finally eliminated based on misleading titles and abstracts which brings the total to 8 articles. Articles were then placed in a table that shows if the Universal Salt Iodization policy was implemented on a mandatory or voluntary basis and the improvements that were seen in those countries. IODINE AND HASHIMOTO’S THYROIDITIS 31

Figure 4. Flowchart for the second initial search in Systematic Literature Review

Steps on the flow chart 1. Identification a. Articles identified through the database (n=6,100) b. Duplicates removed (n=2) 2. Screening a. Articles screened (n=6,098) b. Records excluded (n=6,090); based on date (n=25), based on research strategy (n=6,007), based on abstract/title (n=59) 3. Included a. Articles used in the systematic review (n=8)

IODINE AND HASHIMOTO’S THYROIDITIS 32

Table 3. Universal Salt Iodization Policy and Iodine Deficiency Study Mandatory Voluntary Conclusion USI USI (Gärtner, 2016) X 33% of children and 32% of adults were still showing signs of mild to moderate iodine deficiency (Pedersen et al., 2007) X No improvement with fortification at 8 ppm. Increased to 13 ppm and noticed small improvements. (Gunnarsdottir & Dahl, 2012) X In 2004 the median UIC increased to 101 ug/l. Children and 40-45-year- old women were still below recommended levels (Olivieri, 2017) X Iodine levels have increased, but Italy is still iodine deficient. (Zhao & Haar, 2004) X The percentage of households implementing iodized salt increased from 43.1% in 1995 to 89.0% in 1999. (Sun, et al., 2017) X With this follow up study, iodine deficiency disorders have been eliminated in 28 out of the 31 provinces. (Zahidi, et al., 2016) X Morocco was severely iodine deficient before the policy. After voluntary implementation, they were moderately iodine deficient. (Doggui, et al., 2016) X All commercial salt was to be iodized, but salt used in household did not have to be iodized.

There has been a significant decrease in the prevalence of iodine deficiency since the policy has been implemented, but more work needs to be done. In countries such as Germany, the Universal Salt Iodization policy is voluntary. In 2016, it was reported that 33% of children and 32% of adults were still showing signs of mild to moderate iodine deficiency (Gärtner,

2016).

Denmark is another country that had implemented this policy voluntarily. In 1998, only

8 ppm of iodine was introduced but it showed to be ineffective (Pedersen et al., 2007). After two IODINE AND HASHIMOTO’S THYROIDITIS 33 years, iodine fortification became mandatory at 13 ppm. With this increase, they noticed a decrease in the prevalence of iodine deficient people (Pedersen et al., 2007). Before iodine fortification in Denmark, the median urinary iodine concentration was 61ug/l (Gunnarsdottir &

Dahl, 2012). When the policy became mandatory in 2000, all salts used in bread and for household uses were fortified. In 2004 the median UIC increased to 101 ug/l (Gunnarsdottir &

Dahl, 2012). Even though there was a substantial increase in the concentration of iodine, children and 40-45-year-old women were still below recommended levels (Gunnarsdottir &

Dahl, 2012).

Italy is another country that was using the Universal Salt Iodization policy voluntarily. In

2009, the Italian National Institute of Health created a supplemental program to monitor salt iodization; Italian National Observatory for Monitoring Iodine Prophylaxis (OSNAMI) (Olivieri,

2017). These efforts have helped increase the amount of iodine in diets, however, Italy is still mild iodine deficient.

In China, iodine deficiency was a severe public health issue since 1930. Due to the severity of iodine deficiency, 5 – 15% of children suffered from mild retardation (Sun, et al.,

2017). Along with the Universal Salt Iodization policy, China created the Chinese Iodine

Deficiency Disorders Elimination Program to reduce the amount of iodine deficiency. The percentage of households implementing iodized salt increased from 43.1% in 1995 to 89.0% in

1999 (Zhao & Haar, 2004). When a follow-up study was done in 2017, iodine deficiency disorders have been eliminated in 28 out of the 31 provinces (Sun, et al., 2017). The reasons why the programs were so successful was due to the high-level political commitment, the extensive monitoring, and government regulation. IODINE AND HASHIMOTO’S THYROIDITIS 34

Morocco implemented the Universal Salt Iodization policy in 1995 to decrease the amount of iodine deficiency disorders. Before the policy was implemented, Morocco was a severely iodine deficient country. In a study done in 2016, it was noted that urban areas the amount of iodized salt was higher than in rural areas (Zahidi, et al., 2016). They saw some improvement in the levels of iodine, however, Morocco is still considered to be iodine deficient, and more work needs to be done to fully implement the policy (Zahidi, et al., 2016).

Before Tunisia adopted the Universal Salt Iodization policy twenty years ago, they were a mildly iodine deficient country. Instead of introducing this policy on a mandatory basis, they required that all commercialized salt in the country be iodized (Doggui, et al., 2016). Even though Tunisia requires universal iodization, iodized salt used in households does not meet the requirements set by the WHO (Doggui, et al., 2016). Overall, progress has been made by the policy to make Tunisia an iodine deficient free country.

Discussion Approximately 2 billion people around the globe have either mild, moderate, or severe levels of iodine deficiency (Biban & Lichiardopol, 2017). Iodine is a global health problem due to the many health consequences that it causes. Miscarriages, stillbirths, brain damage, mental abnormalities, and damage to the thyroid are all preventable if enough iodine is ingested. These consequences are what lead global health officials to create and implement the Universal Salt

Iodization Policy. The UN has six goals for this policy: eliminating extreme poverty and hunger, achieving universal primary education, promoting gender equality, reducing child mortality, improving maternal health, and developing a global partnership for development. By using

Huynen’s globalization and health conceptual framework, the implementation of the Universal

Salt Iodization policy can improve rates of iodine nutrition worldwide. Due to the increase in economic development, there has been an increase in food trade which has improved the rates of IODINE AND HASHIMOTO’S THYROIDITIS 35

food insecurity. Since the Universal Salt Iodization policy is not mandatory worldwide, there is no regulation on the amount of iodine being consumed.

Countries such as Germany, Italy, Morocco, and Tunisia have used the Universal Salt

Iodization policy voluntarily. Despite the progress made to improve iodine levels, these

countries are still moderately iodine deficient. Denmark also introduced the policy voluntarily

and progress was seen. However, the country still showed high levels of iodine deficiency until

the policy became mandatory. Results from Gunnarsdottir & Dahl, Zhao & Haar, and Sun, et al.,

showed that with mandatory implementation of the USI policy, iodine deficiency was eliminated

faster.

Hashimoto’s thyroiditis is an autoimmune disorder that attacks the thyroid and various factors can cause this disease. Factors such as sex, pre-existing conditions, genetics, and various environmental triggers have been shown to increase the risk in developing Hashimoto’s thyroiditis. Women are at more of a risk than men in developing Hashimoto’s thyroiditis and this is due to two factors. The number of immune-related genes located on the X chromosome and the number of hormonal changes that women experience (Zaletel & Gaberscek, 2011).

Those that are diagnosed with an autoimmune disease such as lupus or type 1 diabetes are 25% more likely to develop another disease such as Hashimoto’s thyroiditis. Genetics plays an important role in the development of Hashimoto’s thyroiditis. They attribute 80% of the likelihood of developing the autoimmune disease. The AITD genes are HLA-DR, CD40, cytotoxic T lymphocyte-associated factor (CTLA-4), protein tyrosine phosphate 22 (PTPN22), thyroglobulin (Tg) and thyroid-stimulating receptor (TSHR) (Tomer & Huber, 2009). These genes can be modified due to various environmental factors such as drugs, infections, chemicals, and iodine. Drugs that are used to treat chronic hepatitis and melanoma have also been shown to IODINE AND HASHIMOTO’S THYROIDITIS 36

trigger Hashimoto’s thyroiditis. Viral infections such as herpes simplex virus release pro-

inflammatory mediators that can lead to the activation of T-cells in those that are prone to developing autoimmune diseases (Desailloud & Hober, 2009). Chemicals used for industrial applications such as polyaromatic hydrocarbons or polyhalogenated biphenyls have also been shown to trigger thyroid autoimmunity. A slight change in the amount of iodine consumed can trigger an autoimmune response in those that have a genetic predisposition to developing an autoimmune disease. Iodine can either create dysfunction in the production of thyroid hormones or causes inflammation which attracts immune cells to the thyroid.

In 2018, it was reported that the incidence of Hashimoto’s thyroiditis is 1.5 cases per

1000 people and the rates are continuing to increase. This disease is difficult to diagnose and if not treated the consequences can be determinantal. Overtime Hashimoto’s thyroiditis can increase the risk of developing heart conditions, congenital defects, depression, and cancer which can place a finical burden on a family.

This literature review looked into studies that focused on iodine and Hashimoto’s thyroiditis. Studies in Italy, Denmark, and Germany showed that with an increase in the consumption of iodine that the prevalence of Hashimoto’s thyroiditis also increased. The study in Italy considered family history before they began. They gave participants a questionnaire that included any personal or family history of thyroid disease. During the analysis, it was noted that the case study in Italy used two different assays to measure thyroid antibodies. The assay used in

2010 was more sensitive in detecting antibodies than in 1995 which could have attributed to the

11% increase in antibodies. The study in Denmark did not look in family history for its participants and they also noticed that the positive TPO-AB in the first cohort was negative when IODINE AND HASHIMOTO’S THYROIDITIS 37

they were re-analyzed with the results from the second cohort, which could have increased in

thyroid antibodies.

The comparative study between Iceland and Denmark showed how different levels of

iodine consumption affect the prevalence of Hashimoto’s thyroiditis. Iceland is reported to have

higher levels of iodine intake, while Denmark has lower iodine levels (Laurberg, et al., 1998).

Even though Denmark had a higher prevalence of Hashimoto’s thyroiditis, Iceland also reported

some cases of the autoimmune disease which shows that iodine levels have some sort of effect

on Hashimoto’s thyroiditis. This study also took a family history of thyroid diseases for every

participant.

The study in China also gave a questionnaire to the participants in their study that asked

if there are any thyroid diseases in the family as well as any medication for the disease. The

study in China did show a significant difference between the regions with iodine deficiency and

excess iodine, however, thyroglobulin levels were not available for subjects with high levels of thyroglobulin antibodies and there was no pre-iodine fortification data present.

Case studies in Morocco and Sri Lanka showed an increase in TPO-Ab and Tg-Ab after the implementation of iodized salt. However, in Morocco, the TPO-Ab and Tg-Ab levels returned to baseline after one year. The case study in Sri Lanka reported that levels had decreased significantly after three years. With this study, there was no pre-iodine fortification data on thyroid antibodies present.

When reviewing the literature, it seems that there is an underlying factor as to why the rates of Hashimoto’s thyroiditis are increasing with both iodine deficiency and excess levels of iodine. This can be because iodine is a modifier for Hashimoto’s thyroiditis and not the actual cause of the disease. IODINE AND HASHIMOTO’S THYROIDITIS 38

Limitations

The limitations of this study are the amount of research surrounding iodine intake and the increase in the prevalence of Hashimoto’s thyroiditis. Even though the initial literature search yielded 453,284 articles, only 7 articles contained information regarding iodine levels and the autoimmune disease. Since the Universal Iodine Fortification policy has been implemented, there has been progress made in lowering the rates of iodine deficiency. However, with the global prevalence of the disease rising, more research exploring the relationship between the two is needed.

Conclusion

Genetics plays a major part in the development of autoimmune diseases, specifically

Hashimoto’s thyroiditis. However, there are other environmental factors, such as iodine consumption that can play a role. Dietary iodine is extremely important to the overall health of a person. If those levels drop or go above normal, there can be repercussions. Some of the consequences are hyperthyroidism, hypothyroidism, mental and developmental issues in children. Global policy, globalization, and socioeconomic status all play a part in the iodine levels in each country. The Universal Salt Iodization policy was created as a global health initiative to lower the rates of iodine deficiency and the disorders surrounding iodine deficiency such as goiter, cretinism, and impaired mental development. When this policy has been applied on a mandatory level it is more successful than if it was applied on a voluntary level. Three out of the eight studies that implemented the USI policy on a mandatory basis saw more improvement in the rates of iodine deficiency than those that were voluntary.

However, looking at the case studies it shows that excess and deficient levels of iodine are modifying the rates of Hashimoto’s thyroiditis. With the number of people that are suffering IODINE AND HASHIMOTO’S THYROIDITIS 39 from iodine related diseases and Hashimoto’s thyroiditis, it is recommended that more research exploring the relationship between the two is needed as well as monitoring iodine levels worldwide due to the policy.

IODINE AND HASHIMOTO’S THYROIDITIS 40

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Appendix

Table 1. Studies with various iodine levels and Hashimoto’s thyroiditis Study Country Objective Methods Results Conclusion (Laurberg, 1998) Iceland & To study the Comparative Study. TSH: Iceland: 150 Both low and Denmark importance of ug/L high iodine population iodine Age: 66-70 year- Denmark: 38 ug/L intake levels intake level and old TgAB/TPOAB: correlate to a the prevalence of Iceland: n: 100 Twice as high in high prevalence various thyroid High iodine levels Denmark than rate of thyroid abnormalities in Denmark: n: 423 Iceland abnormalities. elderly subjects. Low iodine levels P < 0.01 Twice as high in women in both countries P < 0.05 (Teng, 2006) China To examine the Five year follow up Prevalence of More than effect of regional study. (1999 – autoimmune adequate or differences in 2004) thyroiditis differed excessive iodine intake on significantly among iodine intake the incidence of Three regions with the three countries may lead to thyroid disease. different iodine x2 = 18.4, P <0.001 hypothyroidism levels: Panshan, and mildly deficient; between Panshan and autoimmune Zhangwu, more Zhangwu thyroiditis. than adequate; and x2 = 8.7, P = 0.003 Huanghua, excessive. between Panshan and Huanghua x2 = 18.8, P < 0.001

IODINE AND HASHIMOTO’S THYROIDITIS 50

Table 2. Studies with iodine fortification and rates of Hashimoto’s thyroiditis

Study Country Objective Methods Results Conclusion (Rink, et al., 1999) Germany To determine the Two groups. One Group that Higher doses of effect of iodine treated with iodine, received 1.53 mg iodine cause and fortification on one with of iodine/week increase in Hashimoto’s Hashimoto’s saw 4x higher Hashimoto’s, thyroiditis thyroiditis incidence of however a low- Hashimoto’s daily dose is more thyroiditis sustainable (Zimmermann, et Morocco To determine is Rif Mountains in Significant No patients al., 2003) introduction of northern Morocco. increase in thyroid developed clinical iodized salt antibodies at the evidence of thyroid induces thyroid Severely iodine 20- and 40-week autoimmune autoimmunity. deficient. check P < 0.0001 disease.

Measurements 52-week check: taken before salt only 1% of the iodization, at 10, children had 20, 40, and 52 elevated levels of weeks after. TPO-Ab but did not develop Hashimoto’s thyroiditis while the other children’s TPO-Ab returned to baseline. (Pedersen, 2011) Denmark To measure the Two cross- TPO-AB: Prevalence of both concentrations of sectional studies C1: 14.3% TPO-AB and Tg- thyroid antibodies before (C1) iodine C2: 23.8% Ab was higher 4-5 in the Danish fortification (1997- P < 0.001 years after a population before 1998) cautious IF salt was and after after (C2) (2004- Tg-Ab: introduced in mandatory 2005) C1: 13.7% Denmark. iodization of salt. C2: 19.9% P < 0.001 (Lombardi, 2013) Italy To verify the 1995: n: 1,411 1995: Iodine: 55 Iodine intake effects of voluntary 2010: n: 1,148 ug/L TgAb: 12.6% strongly affected iodine prophylaxis Excluded: HT: 3.5% the pattern of in a small rural Subjects with thyroid diseases. community positive 2010: Iodine: 98 (Pescopagano, TgAB/TPOAB. ug/L The benefits of Italy) Pregnant/lactating TgAb: 19.5% correcting iodine women. HT: 14.5% deficiency far . outweigh the risk P < 0.0001 of developing thyroid autoimmunity.

IODINE AND HASHIMOTO’S THYROIDITIS 51

Table 3. Universal Salt Iodization Policy and Iodine Deficiency

Study Mandatory Voluntary Conclusion USI USI (Gärtner, 2016) X 33% of children and 32% of adults were still showing signs of mild to moderate iodine deficiency (Pedersen et al., 2007) X No improvement with fortification at 8 ppm. Increased to 13 ppm and noticed small improvements. (Gunnarsdottir & Dahl, 2012) X In 2004 the median UIC increased to 101 ug/l. Children and 40-45-year- old women were still below recommended levels (Olivieri, 2017) X Iodine levels have increased, but Italy is still iodine deficient. (Zhao & Haar, 2004) X The percentage of households implementing iodized salt increased from 43.1% in 1995 to 89.0% in 1999. (Sun, et al., 2017) X With this follow up study, iodine deficiency disorders have been eliminated in 28 out of the 31 provinces. (Zahidi, et al., 2016) X Morocco was severely iodine deficient before the policy. After voluntary implementation, they were moderately iodine deficient. (Doggui, et al., 2016) X All commercial salt was to be iodized, but salt used in household did not have to be iodized.

IODINE AND HASHIMOTO’S THYROIDITIS 52

Figure 1

Table 2. Recommended Dietary Allowance (RDA) for Iodine Life Stage Age Males (ug/day) Females (ug/day) Infants 0-6 months 110 (AI) 110 (AI) Infants 7-12 months 130 (AI) 130 (AI) Children 1-3 years 90 90 Children 4-8 years 90 90 Children 9-13 years 120 120 Adolescents 14-18 years 150 150 Adults 19 years or older 150 150 Pregnancy All ages - 220 Breast-feeding All ages - 290

Figure 1 | Recommended Dietary Allowance (RDA) for Iodine (Iodine, 2019).

IODINE AND HASHIMOTO’S THYROIDITIS 53

Figure 2

Figure 2| The Iodine Global Network. Global scorecard of iodine nutrition in 2019 based on median urinary iodine concentration in school-age children.